Cocaine abuse continues to be a significant problem in the U S. The research proposed in Project 3 is designed to investigate the behavioral and neuropharmacology of cocaine as it relates to cocaine abuse. One series of studies is designed to investigate pharmacological modification of the reinforcing effects of cocaine in monkeys. We will examine the interaction of cocaine with drugs that may reduce its self-- administration via an antagonist or an agonist action. In addition, we will investigate the interaction of cocaine with other drugs of abuse. Our hypothesis is that the reinforcing effects of drugs of abuse are potentiated when they are combined. The second series is designed to examine pharmacological modification of the discriminative stimulus (DS) effects of cocaine, an animal model of their subjective effects in humans. We will examine the interaction of cocaine with drugs that may reduce it's DS effect via an antagonist or an agonist action. In addition, we will examine the interaction of cocaine with other drugs of abuse. Our hypothesis is that the DS effects of cocaine are potentiated in combination with other drugs of abuse. The third series will continue our investigation of the behavioral effects of prolonged exposure to cocaine. Both tolerance and sensitization have been reported to develop when cocaine is administered repeatedly. We propose to investigate the influence of conditions of cocaine administration (i.e., continuous or intermittent) on the development of tolerance/sensitization to the effects of cocaine on operant behavior in rhesus monkeys. We will also examine changes in sensitivity to drugs with selective actions in the CNS (e.g., dopamine agonists) to collect information relevant to the CNS changes that may underlie our behavioral observations. The research in the first 2 series will increase our knowledge of the CNS actions involved in the stimulus effects of cocaine, suggest therapeutic interventions for cocaine abuse and provide insights into the abuse of drug combinations. The third series will increase our understanding of the effects of longterm exposure to cocaine. An important aspect of this proposal is our ability to study all of these effects in a single species, the rhesus monkey, and therefore to directly compare results from each of the 3 paradigms. The information gained from this research should contribute significantly to our understanding of the behavioral pharmacology of cocaine abuse.